Family: Picornaviridae

Genus: Cardiovirus

Distinguishing features

The genus is distinguished on the basis of genetic characters. The cardiovirus L protein is a unique picornavirus protein with Zn-finger domain (C-x-H-x₆-C-x₂-C) playing key roles in (i) the regulation of virus translation, (ii) phosphorylation of nucleoporins, and (iii) inhibition of interferon synthesis. It binds the cellular Ran-GTPase. The cardiovirus 2A protein contains an NPG↓P motif and additional domains facilitating nucleolar localization, rRNA binding, and inhibition of cap-dependent cellular mRNA translation. 

Virion 

Morphology

The crystal structures of mengovirus (Cardiovirus A), Theiler's murine encephalomyelitis virus (TMEV, Cardiovirus B) and Saffold virus 3 (Cardiovirus B) have been resolved (Grant et al., 1992, Krishnaswamy and Rossmann 1990). Empty capsids are seen only rarely, if ever. When compared by mean wall thickness, surface unevenness, and chain length of the major proteins, the cardiovirus capsid is intermediate between that of the enteroviruses and aphthoviruses. In place of a continuous, circular canyon seen in enteroviruses, there is a five-fold repeated pit. There is no pocket factor. 

Physicochemical and physical properties

Virion buoyant density in CsCl is 1.33–1.34 g cm^-3. Virions are moderately stable to acidic pH. 

Nucleic acid

Genome (Bae et al., 1989, Ohara et al., 1988, Duke et al., 1992, Law and Brown 1990): c. 7,730–8,530 nt (5′-UTR: up to 1,451 nt, ORF: 6,879–6,924 nt, 3′-UTR: 121–144 nt). Encephalomyocarditis (EMC) viruses have a poly(C) tract of variable length (usually 80–250 nt) about 150 nt from the 5′-terminus of the viral RNA, while the other cardioviruses lack this feature. EMC viruses have two pseudoknots 5′ to their poly(C) tracts. The IRES is of type II. The cre is located in the 1B region of both EMCV-1 and TMEV. The nt sequence identity over the entire genome for different species of the genus Cardiovirus is more than 50% (e.g. TMEV has 54% nt sequence identity to EMCV-1). 

Genome organization and replication

Genome layout

Cardiovirus A, Cardiovirus B, Cardiovirus D, Cardiovirus E, Cardiovirus F: VPg+5′-UTR^IRES-II-[L-1A-1B-1C-1D-2A^npgp/2B-2C/3A-3B-3C-3D]-3′-UTR-poly(A)

Cardiovirus C: VPg+5′-UTR^IRES-II-[L-1A-1B-1C-1D/2A-2B-2C/3A-3B-3C-3D]-3′-UTR-poly(A)

The deduced polyproteins range from 2,292–2,307 aa. The viral genome encodes a leader (L) protein which lacks proteolytic activity. The 2A protein of members of the species Cardiovirus A and Cardiovirus B is c. 140 aa and causes NPG↓P-mediated polypeptide chain interruption at its C-terminus. The orthologous 2A protein of Boone cardioviruses (Cardiovirus C) is shorter (127 aa) and lacks an NPG↓P motif. 

Biology

Encephalomyocarditis viruses have been isolated from over 30 host species including mammals, birds and invertebrates. Clinical manifestations include encephalitis and myocarditis in mice and many other animals. TMEV can be divided into two biological subgroups which both infect mice; one causes an acute and fatal polioencephalomyelitis and the other causes a chronic persistent demyelinating infection of the white matter. VHEV was isolated (in mice) from a person suffering from a degenerative neurological disease (Vilyuisk encephalitis). However, the virus was extensively passaged in mice during the 1950’s and it is not clear if it is of human or mouse origin. Thera virus has been isolated from clinically normal rats. Saffold viruses have been isolated from humans, especially children, and have been associated with both respiratory disease and gastroenteritis. Boone cardioviruses were detected in rats. Cardiovirus infection does not cause cleavage of the host eIF-4G. The cellular receptor used by EMCV to attach to murine vascular endothelial cells has been identified as VCAM-1. However, in human cell lines an as yet unidentified sialoglycoprotein(s) is used. EMCV binds to human erythrocytes via glycophorin A. Low-neurovirulence TMEV’s use sialic acid to attach to mammalian cells, while glycosaminoglycan heparan sulphate is involved in the attachment of high-neurovirulence TMEV’s. Thirty-two genetic types are distinguished by means of phylogenetic analysis (Cardiovirus A: 2 types; Cardiovirus B: 14 types, Cardiovirus C: 3 types, Cardiovirus D: 11 types, Cardiovirus E: 1 type, Cardiovirus F: 1 type). 

Antigenicity

Four independent antigenic sites have been described. There is no evidence of an N-D conversion, nor of 'A' particles. The species Cardiovirus A consists of two types (Dick 1949, Warren et al., 1949, Philipps et al., 2012). However, the species Cardiovirus B comprises 15 genetic types, Theiler’s murine encephalomyelitis virus (TMEV), Vilyuisk human encephalomyelitis virus (VHEV), thera virus (formerly named Theiler-like virus of rats), Saffold virus (SAFV) types 1 to 11, and genet fecal theilovirus (from Geneta geneta) (Ohara et al., 1988, Pevear et al., 1988, Pevear et al., 1987, Liang et al., 2008, Ohsawa et al., 2003, Jones et al., 2007, Chiu et al., 2008, Abed and Boivin 2008, Bodewes et al., 2014). There is no cross-neutralization between TMEV and VHEV; however, the antigenic relationships between these and thera, Saffold and genet fecal theiloviruses is presently not known. Species Cardiovirus C consists of two types. 

Derivation of names

Cardiovirus: from Greek kardia, "heart"

Species demarcation criteria

Members of a species of the genus Cardiovirus:

• are less than 30% divergent in polyprotein aa sequence
• are less than 40% divergent in P1 aa sequence
• are less than 30% divergent in 2C + 3CD aa sequence
• share a natural host range
• share a common genome organization

The divergence (number of differences per site between sequences) of members of different Cardiovirus species ranges from 0.38–0.51 for P1 and 0.4–0.47 for 3CD. 

Related, unclassified viruses

Virus names and virus abbreviations are not official ICTV designations. 

* partial genome

Phylogenetic analysis suggests that these two viruses may each belong to a novel species within the genus.